Treatment with gene-edited cell therapies not associated with subsequent cancer risk
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Patients with cancer who received genetically modified immune effector cells did not demonstrate increased risk for developing subsequent malignancies, according to results of a retrospective study.
The analysis — presented during the virtual American Society of Gene & Cell Therapy Annual Meeting — yielded no evidence of genotoxicity among patients treated with a variety of gene-edited immune effector cell therapies over the past 3 decades.
“Over time, a number of immune cells have been genetically modified, and we have seen promising results with many of these agents,” David Steffin, MD, assistant professor in the hematology and oncology section within the department of pediatrics at Baylor College of Medicine, said during a presentation. “A longstanding concern has been the long-term risk for genotoxicity due to the use of retroviral vectors and the risk for genetic recombination.”
Early results from gene therapy trials raised concerns about genotoxicity, Steffin said.
“This hasn't been observed for T-cell therapies using newer lentiviral and retroviral vectors,” he added.
Steffin and colleagues performed a retrospective chart review of 356 patients (median age, 24 years) who received at least one infusion of retroviral vector-based, genetically modified immune effector cell therapies as part of 28 investigator-initiated clinical trials conducted at Center for Cell and Gene Therapy at Texas Children’s Hospital and Houston Methodist Hospital.
Fifty-six percent of patients had a hematologic malignancy as their primary diagnosis, compared with 44% who had solid tumors. Fifty-seven percent of patients had a previous hematopoietic stem cell transplant.
Researchers sought to review the center’s 24-year history of providing genetically modified immune effector cell therapies and document the occurrence of subsequent malignancies in patients over time, Steffin said.
The study included more than 924 patient-years of follow-up data.
Results showed 12 patients developed a total of 16 subsequent malignancies, for an incidence rate of 3.7%. Four patients had two subsequent malignancies each after receiving cell therapy infusions.
Subsequent malignancy types included myelodysplastic syndrome (n = 3), acute myeloid leukemia (n = 1) and T-cell lymphoblastic lymphoma (n = 1), in addition to a variety of solid tumors (n = 11).
Eleven different types of gene-edited immune effector cells were used across the 28 trials, including seven different chimeric antigen receptor T-cell therapies.
The analysis found no relationship between subsequent malignancy type and the cell therapy used in the trial.
Evidence of genotoxicity was evaluated using polymerase chain reaction analysis to detect cell therapy transgenes. Researchers found no transgene copies among 10 tumor biopsies available for subsequent analysis.
Steffin and colleagues also conducted replication complement retroviral testing on peripheral blood, which yielded negative results for all 13 patients available for evaluation.
The researchers compared 5-year cumulative incidence of subsequent malignancies with that of a control group of patients with lymphoma who received nongenetically modified Epstein-Barr virus-specific cytotoxic T lymphocytes at the same center. The results showed no increased risk for subsequent malignancies using Gray’s test.
“Most subsequent malignancy types were consistent with those seen after hematopoietic stem cell transplant and chemotherapy,” Steffin said. “Long-term follow-up of patients will need to continue as we optimize our immune effector technologies to ensure they don't increase the risk [for] subsequent malignancies in the future.”
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